Dental resptorative cement pastes

ABSTRACT

Compositions that are useful and unique as dental remineralizers and dental cements, as well as methods for their use, are disclosed. The compositions are mixtures of at least two sparingly soluble calcium phosphates that are present in excess and a dilute aqueous solution approximately saturated with respect to the calcium phosphates such that they are both in near equilibrium with the saturated solution. The saturated solution is also supersaturated with respect to hydroxyapatite. Therefore, this basic constituent of dental enamel is continuously precipitated from the saturated solution and is available for the remineralization of 
     The invention described herein was made in the course of research partially supported by a grant from the National Institute of Dental Research.

The invention described herein was made in the course of researchpartially supported by a grant from the National Institute of DentalResearch.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This application is a continuation-in-part of the copending application,Ser. No. 373,157, filed on Apr. 29, 1982.

This invention relates to certain combinations of sparingly solublecalcium phosphates that are unique in their application asremineralizers of caries lesions in dental enamel and partiallydemineralized dentin and cementum and in their application as dentalcements. When used as a remineralizer the present invention not onlyprevents tooth decay, but can also restore the lesions caused by dentalcaries. The dental cements of the present invention have a variety ofdental applications, but are most useful where contact between thecement and living tissue is required.

BACKGROUND OF THE INVENTION

When an incipient lesion or cavity develops on the surface of a tooth,the dentist traditionally fills the cavity that forms. This proceduremay prevent the decay from spreading further, but does not restore thetooth to its original state. A considerable amount of research, however,has recently been directed to the remineralization of incipient dentallesions. The object of remineralization is to deposit Ca₅ (PO₄)₃ OH,known as hydroxyapatite, on the caries lesion such that the dentalenamel incorporates the hydroxyapatite into its structure at the pointof lesion. (Tooth and bone minerals are impure forms of hydroxyapatite.)Thus, remineralization prevents further tooth decay and restores thetooth.

Remineralization of tooth enamel has been carried out experimentallyboth in vivo and in vitro. These studies have concentrated on theremineralizing properties of saliva and synthetic solutionssupersaturated with respect to hydroxyapatite. Two recent articles thatgive a good overview of this research are Briner et al, "Significance ofEnamel Remineralization," J. Dent. Res. 53: 239-243 (1974); andSilverstone, "Remineralization Phenomena," Caries Res. II (Supp. 1):59-84 (1977). Additional experimental work in the areas ofremineralization of calcium phosphate biomaterials may be found inGelhard et al, "Rehardening of Artificial Enamel Lesions in vivo,"Caries Res. 13: 80-83 (1979); Hiatt et al, "Root Preparation I.Obduration of Dentinal Tubles in Treatment of Root Hypersensitivity," J.Periodontal. 43: 373-380 (1972); LeGeros et al, "Apatitic CalciumPhosphates: Possible Dental Restorative Materials," IADR Abstract No.1482 (1982); Pickel et al, "The Effect of a Chewing Gum ContainingDicalcium Phosphate on Salivary Calcium and Phosphate," Ala. J. Med.Sci. 2: 286-287 (1965); Zimmerman et al, "The Effect of RemineralizationFluids on Carious Lesions in vitro," IADR Abstract No. 282 (1979); andU.S. Pat. Nos. 3,679,360 (Rubin) and 4,097,935 (Jarcho).

Generally, the supersaturated solutions or slurries used forremineralization experiments have been prepared from a single form ofcalcium phosphate. When a caries lesion is flooded with one of thesesupersaturated solutions, the calcium and phosphate ions in the form ofprecipitated hydroxyapatite remineralize the lesion. However, thesesolutions are impractical for use on patients for several reasons.First, the amount of calcium and phosphate ions available forremineralization in these supersaturated solutions is too low. It takesapproximately 10,000 unit volumes of the usual supersaturated solutionto produce one unit volume of mineral. Thus, remineralization by thismethod requires both an excessive volume of fluid and an excessivenumber of applications. The supersaturated solutions are inherentlylimited in this respect because they cannot maintain theirsupersaturated state. When the hydroxyapatite precipitates out to thepoint where the solution is no longer supersaturated, new supersaturatedsolution must be introduced or the remineralization process stops.

An example of another kind of problem is described in Levine,"Remineralisation of Natural Carious Lesions of Enamel in vitro," Brit.Dent. J., 137: 132-134 (1974), where a phosphate buffer solutionsaturated with respect to CaHPO₄.2H₂ O (dicalcium phosphate dihydrate orbrushite) and containing some fluoride was applied to dental enamel. Toeffect complete mineralization, exposure to the solution for threeminutes every hour for 24 hours was necessary. Though the articlesuggested that this exposure could be achieved by use of two minutemouth rinses twice daily over the course of a year, this was admitted bythe author to be an impractical procedure.

Another problem with single calcium phosphate slurries is that as thehydroxyapatite precipitates out of solution, the pH of the solutionchanges. Unless the old solution is removed from contact with the toothmaterial, the solution may become too acidic or alkaline and damage thedental tissue.

Another problem with known remineralization techniques is that theremineralization may stop before the lesion is completely remineralizeddue to build up of the remineralized tooth material in or on the outerlayer of the tooth's surface. This build up occurs when the rate ofremineralization is too fast and prevents the diffusion of the mineralinto the deeper regions of the lesion, thus thwarting the fullremineralization of the tooth.

There is a need for a method of remineralizing dental enamel that doesnot require excessive amounts of solution and inordinately long orfrequent exposure times. Furthermore there is a need for aremineralization solution or slurry that can maintain a relativelyconstant pH and remain in a supersaturated state so that hydroxyapatitemay be precipitated for a substantial period of time.

In the area of dental cements, the prior art shows an array ofcompounds. Some cements, however, irritate the pulp and are unsuitablefor applications where the cement must come in contact with exposedpulp. Guide to Dental Materials and Devices, 7th Ed. (ADA 1974) p. 49.One solution to this problem is a cement made of materials similar incomposition to tooth and bone mineral, since this would not irritate theliving tissue.

The use of β-Ca₃ (PO₄)₂ was suggested for pulp capping in Driskell etal, "Development of Ceramic and Ceramic Composite Devices forMaxillofacial Application," J. Biomed. Mat. Res. 6: 345-361 (1972); andthe use of Ca₄ (PO₄)₂ O was suggested by the inventors in IADR AbstractNo. 120, J. Dent. Res. 54: 74 (1975) as a possible pulp capping agent.As described in the latter, Ca₄ (PO₄)₂ O hydrolyzes to hydroxyapatite.Therefore, use of a calcium phosphate dental cement should provide anon-irritating cement capable of setting to a hard consistency and, whendesired, remineralizing the dental tissue it contacts. Such a cementwould be of great benefit, for example, as a root canal or root surfacecement.

Single calcium phosphate cements, are incapable of setting to a hardconsistency, however, and would suffer from the same drawbacks describedabove for single calcium phosphate remineralizers. They cannot maintaina relatively constant pH and do not have sufficient remineralizationcapacity. Though U.S. Pat. No. 3,913,229 (Driskell et al.) disclosesputty-like pastes containing α-Ca₃ (PO₄)₂,β-Ca₃ (PO₄)₂, CaHPO₄ andmixtures thereof as pulp capping, root canal, and tooth replantingmaterials, it is believed that none of these pastes harden into cements.Furthermore, no remineralization properties are disclosed. Thus, thereis a need for a dental cement that is non-irritating, yet has goodremineralizing capacity coupled with a stable pH.

SUMMARY OF INVENTION

The potential for application of dental remineralization is vast.Approximately 5×10⁸ cavities are filled each year. If these half billioncaries lesions were remineralized rather than being filled as cavities,the general dental health would be increased substantially, sinceremineralization results in a whole tooth. The present invention seeksto provide remineralization compositions and methods that can bepractically applied under a dentist's care and thereby replace the needfor filling of cavities.

Briefly, the present invention relates to compositions forremineralizing caries lesions. The invention concerns a combination ofCa₄ (PO₄)₂ O (tetracalcium phosphate) and at least one other sparinglysoluble calcium phosphate solid in equilibrium or quasi equilibrium witha dilute aqueous solution such that both calcium phosphates are presentin excess and form a slurry. The other calcium phosphates that may beused are CaHPO₄.2H₂ O (dicalcium phosphate dihydrate or brushite),CaHPO₄ (monetite), Ca₈ H₂ (PO₄)₆.5H₂ O (octacalcium phosphate), α-Ca₃(PO₄)₂,β-Ca₃ (PO₄)₂ (tricalcium phosphates), and tricalcium phosphatesmodified by the addition of protons or up to approximately 10% magnesiumby weight (whitlockite). All combinations of these calcium phosphatescan precipitate hydroxyapatite according to the present invention. To doso, however, the two calcium phosphates must be in near equilibrium withthe same saturated solution; furthermore, the saturated solution just besupersaturated with respect to hydroxyapatitie. If these conditions aremet, the above combinations of calcium phosphates will react to formhydroxyapatitie. Since the two calcium phosphates are present in excess,the solution will remain supersaturated with respect to hydroxyapatiteand will continue to precipitate this basic constituent of tooth andbone.

The advantages of a combination of calcium phosphates according to thepresent invention as compared with solutions or slurries of a singlecalcium phosphate are many. Most importantly, the inventive combinationof calcium phosphates in a slurry will remain supersaturated withrespect to hydroxyapatite for a significant period of time. For example,a combination of tetracalcium phosphate and brushite can remain activeas a remineralizer for as long as a week. Thus, a single application ofthis inventive slurry to a caries lesion would suffice for completeremineralization of the afflicted area. This obviates the need forrepeated and lengthy exposures required by previously proposedremineralization systems.

Another significant advantage of the present invention is that thecombination of sparingly soluble calcium phosphates stabilizes the pH ofthe system near the point of equilibrium. This prevents wide swings inpH that might injure the dental enamel or other tissue. A stable pH alsopermits hydroxyapatite to continue precipitating, since hydroxyapatitewill not precipitate at a low pH. Furthermore, the pH of the singularpoint may be altered by the addition of calcium or phosphate containingcompounds to the slurry. This allows the dentist to select the mostbeneficial pH for remineralization.

Another advantage of the present invention is that the rate ofmineralization may be adjusted to the needs of the particular lesion.The addition of simple fuoride compounds will increase the rate ofmineralization. Conversely, high molecular weight crystal growthinhibitors may be added to slow mineralization. These latter compoundsfacilitate the remineralization of the subsurface of a caries lesion byinhibiting the remineralization of the outside surface of the tooth.This allows the hydroxyapatite ions to diffuse into the lesion'ssubsurface and completely remineralize the cavity.

Thus, the present invention provides compositions for theremineralization of caries lesions that are practical for clinical usedue to their large remineralization capacities and stable pH's. The rateand depth of remineralization may be selected by the dentist, therebygiving substantial flexibility to the remineralization process.

The present invention also concerns compounds useful as dental cements.The same combinations of calcium phosphates described above may becombined in a paste, rather than a slurry, and allowed to harden. Theresulting cements are similar in composition to tooth and bone materialand, therefore, are fully compatible with dental tissue. Though thecements of the present invention may be used in any application forwhich conventional dental cements are suitable, the cements of thepresent invention are particularly helpful where contact with livingtissue is required. In addition, these cements provide the uniquecombination of remineralizing properties and hardening characteristicsthat would be especially desirable for a root canal or root surfacecement because they are compatible with, protect and remineralize thesensitive surfaces of exposed roots.

Further objects and features of the invention will become apparent fromthe following description of the preferred embodiments and claims.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a plot of the solubility isotherms of Ca₄ (PO₄)₂ O; CaHPO₄.2H₂O; CaHPO₄ ; Ca₈ H₂ (PO₄)₆.5H₂ O; β-Ca₃ (PO₄)₂ ; and Ca₅ (PO₄)₃ OH at 25°C. in the ternary system of Ca(OH)₂ ; H₃ PO₄ ; and H₂ O.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The sparingly soluble calcium phosphates that are relatively stable atambient temperatures and are, therefore, available for use in theinventive remineralizing slurries and cements include CaHPO₄.2H₂ O;CaHPO₄ ; Ca₈ H₂ (PO₄)₆.5H₂ O; α-Ca₃ (PO₄)₂ ; β-Ca₃ (PO₄)₂ ; tricalciumphosphates modified by protons or up to approximately 10% magnesium byweight; and Ca₄ (PO₄)₂ O. Each of these calcium phosphates has acharacteristic solubility behavior that may be represented by a plot ofthe total concentration of calcium ions at the point of saturationversus the pH of the solution at a constant temperature. (A plot of thetotal concentration of phosphate ions versus pH would be equivalent forthe purposes of the present invention because the concentrations ofphosphate and calcium ions in solution are linked.) The resulting curveis called an isotherm.

When the isotherms for various calcium phosphates are plotted on thesame axes, their solubility behavior relative to each other may bedetermined. Specifically, a calcium phosphate whose isotherm lies abovethe isotherm of another calcium phosphate at a given pH is metastablewith respect to the latter. The point where the isotherms of two calciumphosphates intersect is known as a singular point. In a solution that issaturated with respect to the two calcium phosphates, both calciumphosphates will be in equilibrium with the saturated solution at thesingular point. This means that neither calcium phosphate willprecipitate out of solution, but another calcium phosphate whoseisotherm lies below the singular point can precipitate. The presentinvention relates to combinations of calcium phosphates that formsingular point solutions that are supersaturated with respect tohydroxyapatite.

FIG. 1 is a plot of the solublity isotherms for six calcium phosphatesin the ternary system comprising Ca(OH)₂, H₃ PO₄ and H₂ O at 25° C. They-axis of FIG. 1 represents the total concentration of calcium ions insolution in moles per liter, while the x-axis represents pH. Theisotherms for CaHPO₄.2H₂ O, CaHPO₄, β-Ca₃ (PO₄)₂ and Ca₅ (PO₄)₃ OH arebased, respectively, on the following articles: Gregory et al,"Solubility of CaHPO₄.2H₂ O in the System Ca(OH)₂ -H₃ PO₄ -H₂ O at 5°,15°, 25°, and 37.5° C.," J. Res. Nat. Bur. Stand. 74A: 461-475 (1970);McDowell et al, "Solubility Study of Calcium Hydrogen Phosphate. IonPair Formation," Inorg. Chem. 10: 1638-1643(1971); Gregory et al,"Solubility of β-Ca₃ (PO₄)₂ in the System Ca(OH)₂ -H₃ PO₄ -H₂ O at 5°,15°, 25° and 37° C.," J. Res. Nat. Bur. Stand. 78A: 667-674 (1974); andMcDowell et al, "Solubility of Ca₅ (PO₄)₃ OH in the System Ca(OH)₂ -H₃PO₄ -H₂ O at 5°, 15°, 25° and 37.5° C.," J. Res. Nat. Bur. Stand. 81A:273-281 (1977). The isotherm for Ca₈ H₂ (PO₄)₆.5H₂ O is based on thesolubility product disclosed in Moreno et al, "Stability of DicalciumPhosphate Dihydrate in Aqueous Solutions and Solubility of OctacalciumPhosphate," Soil Sci. Soc. Am. Proc. 21: 99-102 (1960), while theisotherm of Ca₄ (PO₄)₂ O is based on the approximate value of thesolubility product calculated by the inventors.

As can be seen from FIG. 1, not all combinations of calcium phosphateshave singular points. For example, the isotherms of CaHPO₄.2H₂ O andCaHPO₄ never cross at ambient temperature. Therefore, this pair ofcalcium phosphates does not embody the inventive concept of combinationsof calcium phosphates that may each be in equilibrium with the samesaturated solution at their singular point.

There are two additional considerations that limit the choice of calciumphosphates for the present invention. First, the singular point of thetwo calcium phosphates must lie above the isotherm for hydroxyapatite.This insures that a solution that is saturated with respect to the twocalcium phosphates at their singular point will also be supersaturatedwith respect to hydroxyapatite. Thus, hydroxyapatite can precipitate outof the solution and be available for remineralization. Second, thesingular point for the pair of calcium phosphates should preferably notlie too far above the isotherm for CaHPO₄.2H₂ O, since the singularpoint of such a combination might be too unstable for use as aremineralizer or cement. Therefore, although β-Ca₃ (PO₄)₂ and Ca₈ H₂(PO₄)₆.5H₂ O have intersecting isotherms, their singular point lies farabove the isotherm for CaHPO₄.2H₂ O and is probably unsuitable.

The circles in FIG. 1 define singular point compositions for the variouspairs of solids in solution. As can be seen from FIG. 1, the followingcombinations of calcium phosphates are definitely available asremineralizers and cements according to the present invention:CaHPO₄.2H₂ O with β-Ca₃ (PO₄)₂, Ca₈ H₂ (PO₄)₆.5H₂ O, or Ca₄ (PO₄)₂ O;CaHPO₄ with β-Ca₃ (PO₄)₂, Ca₈ H₂ (PO₄)₆.5H₂ O, or Ca₄ (PO₄)₂ O; and Ca₄(PO₄)₂ O with Ca₈ H₂ (PO₄)₆.5H₂ O or β-Ca₃ (PO₄)₂. Additionally, thereare potentially three or four singular point compositions containingα-Ca₃ (PO₄)₂. Likewise, the isotherms of the modified tricalciumphosphates may define additional inventive compositions.

The reason that a singular point composition has such desirableproperties as a remineralizer and cement is that it resists changes inthe pH or composition of the solution by driving itself back to thesingular point whenever the composition or pH changes. For example, iftwo calcium phosphates that possess a singular point were present inexcess in a solution that was more acidic than the pH of the singularpoint, the more basic phosphate would dissolve and cause the more acidicphosphate to precipitate. This process would continue until the pH andthe composition were forced back to the singular point, where the twocalcium phosphates present in excess would both be in equilibrium withthe solution and neither would precipitate out of solution. The reverseprocess would occur if the composition started at a point more basicthan the singular point pH.

When only two salts are present in the solution, the composition of thesolution cannot rise above the isotherm of the more soluble salt or fallbelow the isotherm of the less soluble salt. Furthermore, the solutionwill only be in equilibrium at the singular point. However, theprecipitation of a third salt, such as hydroxyapatite, may drive thecomposition in the direction of the third salt's isotherm. The degree ofdeviation depends upon the relative rates of dissolution andprecipitation of the three salts.

For the purposes of remineralization, it would be undesirable if thesolution's composition deviated too close to the isotherm ofhydroxyapatite since this would lower the rate of precipitation ofhydroxyapatite. However, since the two calcium phosphates are present inexcess, the relative rate of precipitation for hydroxyapatite is likelyto be small when compared to the dissolution and precipitation rates ofthe other two calcium phosphates, and the composition will remain in thevicinity of the singular point. Thus, a slurry containing excessiveamounts of two calcium phosphates having a singular point can remainapproximately at the pH and composition of the singular point despitethe constant production and precipitation of hydroxyapatite. It is thisfeature of the present invention that permits a remineralizing slurry orpaste to remain active as a remineralizer for a substantial period oftime without great shifts in pH or composition.

The combinations of calcium phosphates listed above that have singularpoints all react to form hydroxyapatite. However, these combinationsfall into two distinct classes: those containing Ca₄ (PO₄)₂ O and thosethat do not. Ca₄ (PO₄)₂ O is the most basic calcium phosphate of thepresent invention. Therefore, any of the remaining calcium phosphatesthat are more acidic than hydroxyapatite can react directly withtetracalcium phosphate to form hydroxyapatite. For example,

    Ca.sub.4 (PO.sub.4).sub.2 O+CaHPO.sub.4.2H.sub.2 O=Ca.sub.5 (PO.sub.4).sub.3 OH+2H.sub.2 O;

    Ca.sub.4 (PO.sub.4).sub.2 O+CaHPO.sub.4 =Ca.sub.5 (PO.sub.4).sub.3 OH;

    3Ca.sub.4 (PO.sub.4).sub.2 O+Ca.sub.8 H.sub.2 (PO.sub.4).sub.6.5H.sub.2 O=4Ca.sub.5 (PO.sub.4).sub.3 OH+4H.sub.2 O; and

    Ca.sub.4 (PO.sub.4).sub.2 O+2Ca.sub.3 (PO.sub.4).sub.2 [α,β, or modified]+H.sub.2 O=2Ca.sub.5 (PO.sub.4).sub.3 OH.

However, when both salts are more acidic than hydroxyapatite, the moreacidic salt is a reaction product along with hydroxyapatite. Thus,

    2Ca.sub.3 (PO.sub.4).sub.2 [α,β, or modified]+3H.sub.2 O=Ca.sub.5 (PO.sub.4).sub.3 OH+CaHPO.sub.4.2H.sub.2 O;

    2Ca.sub.3 (PO.sub.4).sub.2 [α,β, or modified]+H.sub.2 O=Ca.sub.5 (PO.sub.4).sub.3 OH+CaHPO.sub.4 ;

    Ca.sub.8 H.sub.2 (PO.sub.4).sub.6.5H.sub.2 O+2H.sub.2 O=Ca.sub.5 (PO.sub.4).sub.3 OH+3CaHPO.sub.4.2H.sub.2 O; and

    Ca.sub.8 H.sub.2 (PO.sub.4).sub.6.5H.sub.2 O=Ca.sub.5 (PO.sub.4).sub.3 OH+3CaHPO.sub.4.

In such cases, the more acidic salt provides a template that removes theacidic phosphate ions by crystallizing the acid salt. The removal of theacidic ions holds the pH of the solution near the singular point andmaintains the supersaturated state of the solution with respect tohydroxyapatite that is necessary for remineralization. However, theselatter reactions are not as advantageous as the combinations includingCa₄ (PO₄)₂ O since one of the calcium phosphates must serve as reactionproduct. This is less efficient in producing Ca₅ (PO₄)₃ OH than the Ca₄(PO₄)₂ O containing compositions. Additionally, the more acidic calciumphosphates that serve as reaction products are not removed from theslurry as the remineralization progresses. Therefore, these combinationsare more detrimental to living tissue than are the Ca₄ (PO₄)₂ Ocontaining combinations.

The reaction approximated by 5Ca₈ H₂ (PO₄)₆.5H₂ O=8Ca₅ (PO₄)₃ OH+6H₃ PO₄+17H₂ O, is of particular interest for remineralization, because undermany conditions the rate of formation of octacalcium phosphate appearsto be much greater than the rate of formation of hydroxyapatite. Sinceoctacalcium phosphate can hydrolyze in situ to hydroxyapatite, theformation of Ca₈ H₂ (PO₄)₆.5H₂ O followed by hydrolysis tohydroxyapatite may be a particularly efficacious method for theproduction of hydroxyapatite in remineralizing solutions. The only knowncombinations of calcium phosphates that definitely can form octacalciumphosphate as a precursor to hydroxyapatite are Ca₄ (PO₄)₂ O withCaHPO₄.2H₂ O and CaHPO₄ since their singular points both lie above theisotherm for Ca₈ H₂ (PO₄)₆.5H₂ O. However, the singular points of α-Ca₃(PO₄)₂ with CaHPO₄.2H₂ O and CaHPO₄ might also form octacalciumphosphate as a precursor to hydroxyapatite.

The pH range of the inventive system may be predetermined by choosing apair of calcium phosphates with an appropriate singular point pH. Forexample, if a pH around 7.5 is desired, one could use the combination ofCaHPO₄.2H₂ O and Ca₄ (PO₄)₂ O. The pH of any slurry or paste may befurther altered by the addition of up to approximately 10% by weight ofsimple calcium or phosphate containing compounds. These compounds changethe pH of the singular point by altering the Ca/P ratio of the solution.Since the chemical potentials of Ca(OH)₂ and H₃ PO₄ have been shown tobe invariant in the presence of additional components at a givensingular point [See Brown, "Solubilities of Phosphates and OtherSparingly Soluble Compounds," from Griffith et al, EnvironmentalPhosphorous Handbook (John Wiley & Sons, New York 1973)], the ratio(Ca²⁺)/(H⁺)² is constant at a given singular point, where theparentheses denote ion activities. Thus, the addition of an acidiccompound, such as HCl, CaCl₂, or Ca(C₂ H₃ O₂)₂, will increase the ionicactivity of Ca²⁺, increase the Ca/P ratio of the singular point andcause the singular point to move to a lower pH. Similar considerationshold for the addition of basic compounds. Examples of suitable base andphosphate containing compounds are NaH₂ PO₄ and (NH₄)H₂ PO₄.

The rate of remineralization may also be adjusted. The addition ofsimple or complex fluoride compounds such that the fluoride content ofthe slurry or paste is up to approximately 3.8% by weight will increasethe rate of precipitation of hydroxyapatite and decrease solubility,thereby providing a control on the body's ability to resorb thematerial. Examples of possible fluoride additives are CaF₂, SrF₂, NaF,Na₂ SiF₆, and Na₂ PO₃ F. Through rapid mineralization is beneficialunder some circumstances, it may cause the remineralization of theoutside surface of an incipient caries lesion and prevent theremineralization of the subsurface region of the lesion. A moderatelyslow remineralization rate would allow all parts of the lesion to behealed. The particular calcium phosphates used will affect the rate ofremineralization. In addition, particle size is a factor since asparticle size increases, the rate of mineralization decreases. Generallythe particle size for remineralization slurries should be greater than 5μm. Thus, to remineralize a deep lesion, a slow remineralizing slurrycould be applied to the tooth by means of a bite block sponge,periodontal pack, cement or rigid gel.

It is also possible to facilitate internal remineralization by etchingthe surface of the tooth such that the remineralizing slurry can contactmore of the lesion's surface at once. Another solution to the problem ofincomplete internal remineralization is the application of highmolecular weight crystal growth poisons or inhibitors onto the toothsurface. Examples of such growth inhibitors are proteoglycans,glycoproteins, polylysine, and protamine. Concentrations of up toapproximately 5% by weight may be added to the remineralizing slurry.These inhibitors prevent the growth of hydroxyapatite crystals at thesurface of the tooth but do not tend to diffuse into the interior of thetooth. Accordingly, they inhibit the remineralization of the carieslesion's surface and prevent the blockage of the channels necessary forthe diffusion of calcium and phosphate ions into the subsurface lesion.

All of the combinations of calcium phosphates described above containingCa₄ (PO₄)₂ O may be used as dental cements. The two main differencesbetween the inventive remineralizers and the inventive cements areparticle size and solid-to-liquid ratio. For use as cements, theselected calcium phosphates should be ground to a finer particle size,preferably less than 5 μm. Additionally, calcium phosphate particles arecombined with much less solution so that a paste is formed rather than aslurry. The paste then hardens to a bonelike consistency.

Porous cements that are especially useful as bone implants or prothesesmay be prepared by combining the calcium phosphates with a highly watersoluble material, such as granular sugar, and subjecting this mixture topressure sufficient to form a compact mass. The water necessary for theinventive reaction is usually contained in the calcium phosphatesthemselves. However, a small amount of water may be added to the mixturebefore pressure is applied in order to facilitate the setting of thecement. The resulting mass is then placed into hot water such that thehighly water soluble material is removed. A porous cement remains thatis readily permeated by organic bone tissue.

The cements of the present invention may be used in place of any of thecements known in the prior art as: (i) cavity bases and liners toprotect the pulp, (ii) materials for capping exposed pulps, (iii)materials to replace or promote regeneration of bone mineral lost due toperiodontal disease, (iv) direct filling materials that have physicalproperties similar to enamel and are adhesiveto enamel and dentin, (v) acement to build up alveolar ridges in edentulous patients, (vi) anendodontic filling material for root canals, (vii) a material to cementretention pins, (viii) a material for filling sockets after a toothextraction, (ix) a replacement of bone that has been removed surgicallyor lost due to trauma, (x) a cement for implanting or replanting teeth,(xi) a luting cement in dentistry and orthopaedic surgery, (xii) aninvestment mold material, (xiii) a material which will promote bonemineral growth in its vicinity, (xiv) a remineralizing polish for use inplace of pumice, and (xv) a root cement for remineralizing anddesensitizing of exposed root surfaces. Since the inventive cements arefully compatible with living tissue, they are especially advantageouswhere contact with dental tissue is necessary. In addition, the cementspossess remineralization capabilities. Thus, the discussion above withrespect to the use of the inventive compositions as remineralizers isfully applicable to their use as cements.

The strength and hardness of the present cements can be controlled bythe particle size of the calcium phosphates, the presence ofhydroxyapatite or Ca₅ (PO₄)₃ F (fluorapatite) as seed or matrixcrystals, and by the use of crystal habit modifiers. These lastcompounds promote the growth of more needle-like apatitic crystals inthe cement. It is believed that a particle size of 1 μm would result ina very strong cement.

The setting time of the present cements may be reduced by adding asizable amount of hydroxyapatite or fluorapatite seed crystals to thepaste as these compounds facilitate crystal formation. This may alsoincrease the hardness of the cement and minimize shrinkage or expansionduring set. Of course, it may be desirable to have some settingexpansion when the paste is used in a cavity preparation in order topromote adhesion to the cavity wall. Such expansion may be achieved bythe addition of β-Ca₃ (PO₄)₂ or up to 1% by weight of crystal habitmodifiers, such as Mg²⁺, Sr²⁺, citrate, phosphonates, carbonate,polyphosphates, sucrose phosphate and phosphocitrate. These modifiersabsorb onto the specific sites of the crystal surfaces during growth,thereby affecting the morphology of the crystals. Additionally,appropriate combinations of varying or "gap-graded" particle sizes wouldpromote setting expansion.

It has also been determined that when fluoride compounds are added tothe liquid or solid phase, the setting time may be reduced further forthe same seed crystal content.

EXAMPLE 1

Two calcium phosphates having a singular point with an appropriate pHare selected. Their singular point should not lie too far above theisotherm for CaHPO₄.2H₂ O and must lie above the isotherm forhydroxyapatite. The calcium phosphates selected may be prepared by themethods described in McDowell et al, "Solubility Study of CalciumHydrogen Phosphate. Ion-Pair Formation," Inorg. Chem. 10: 1638-1643(1971); Gregory et al, "Solubility of β-Ca₃ (PO₄)₂ in the SystemCa(OH₂)-H₃ PO₄ -H₂ O at 5°, 15°, 25° and 37° C.," J. Res. Nat. Bur.Stand. 78A: 667-674 (1974); Moreno et al, "Stability of DicalciumPhosphate Dihydrate in Aqueous Solutions and Solubility of OctacalciumPhosphate," Soil Sci. Soc. Am. Proc. 21: 99-102 (1960); Brown et al,"Crystallography of Tetracalcium Phosphate." J. Res. Nat. Bur. Stands.69A: 547-551 (1965); and Patel et al, "Solubility of CaHPO₄.2H₂ O in theQuaternary System Ca(OH)₂ -H₃ PO₄ -NaCl-H₂ O at 25° C.," J. Rest. Nat.Bur. Stands. 78A: 675-681 (1974). The calcium phosphates may be incrystalline, cryptocrystalline, finely divided, or amorphous form.

Each of the selected, solid calcium phosphates is then ground to thedesired particle size. Generally for remineralization slurries, theparticle size should be greater than 5 μm, since this size prolongs theremineralization potential of the slurry by slowing the remineralizationrate. Larger particle size both slows the reaction rate and retards thesetting or hardening of the slurry.

The ground calcium phosphates are then mixed in excess in a diluteaqueous solution that is either slightly acidic or slightly basic toform a slurry. Examples of appropriate acidic solutions are water and H₃PO₄ or HCl, whle examples of appropriate basic solutions are water andCa(OH)₂ or KOH. The slurry may be applied to the affected area by meansof a bite block sponge, periodontal pack, cement, or rigid gel. Also theslurry may be applied by burnishing, spatulation or packing and coveringby various mechanical means. Additionally, the slurry may be allowed toharden and thereby act as its own cement for holding the remineralizeragainst the afflicted area.

Alternatively, the above remineralizing combinations may be incorporatedinto chewing gum formulations by blending the solid and liquid phaseswith a chewing gum base in the manner practiced in the industry.Similarly, the solid and liquid phases may be combined with the commoningredients of toothpaste. In these cases the particle size of thecalcium phosphates should be such as to avoid grittiness.

In addition, three groups of compounds may be added to the liquid phaseof the remineralization slury. First, fluoride compounds, such as CaF₂,SrF₂, NaF, Na₂ SiF₆, or Na₂ PO₃ F, may be added to increase the rate ofmineralization. Second, calcium and phosphate containing compounds, suchas CaCl₂, Ca(C₂ H₃ O₂)₂, NaH₂ PO₄, or (NH₄)H₂ PO₄, may be added tomodify the Ca/P ratio and pH of the solution'singular point. Third, highmolecular weight crystal growth inhibitors may be added to facilitatethe complete remineralization of the subsurface caries lesions.

EXAMPLE 2

Ca₄ (PO₄)₂ O and CaHPO₄.2H₂ O are ground to an approximate mean particlesize of 40 μm. Two grams of an equimolar mixture of the two solids iscombined with 20 ml of a 5mM H₃ PO₄ solution and mixed to form a slurry.The slurry is then placed on a caries lesion by means of a bite blocksponge. This slurry will maintain a pH in the vicinity of 7.4 andprecipitate hydroxyapatite for almost one week.

EXAMPLE 3

To form a dental cement, Ca₄ (PO₄)₂ O and at least one other calciumphosphate selected from the group consisting of CaHPO₄.2H₂ O, CaHPO₄,Ca₈ H₂ (PO₄)₆.5H₂ O, α-Ca₃ (PO₄)₂, β-Ca₃ (PO₄)₂, and modified Ca₃ (PO₄)₂are ground to a uniform particle size of less than 5 μm so that thesetting time will be reasonable. If some setting expansion is required,"gap-graded" particle sizes may be used. The calcium phosphates are thencombined with the dilute aqueous solutions of Example 1 to form a paste.This paste is then applied by an appropriate means to the affected area.For example, if the cement is to be used as an endodontic fillingmaterial, the paste may be applied by injection or packed with aplugger.

To modify the remineralization properties of the cement, the additivesdescribed in Example 1 may be added to the liquid phase. In addition,crystal habit modifiers may be added to induce more needle-like growthof apatitic crystals. The setting time for a given cement may be reducedby adding hydroxyapatite or fluorapatite seed crystals. The inclusion offluoride compounds will further reduce the setting time.

Setting expansion and shrinkage may be reduced by adding a sizableamount of hydroxyapatite to the paste. Conversely, some settingexpansion may be encouraged by the addition of β-Ca₃ (PO₄)₂ or crystalhabit modifiers.

EXAMPLE 4

Specimens 1-5 shown in Table I were prepared as follows. The two calciumphosphates and hydroxyapatite seed were all ground to a mean particlesize of 5 μm. One gram of a mixture containing equimolar amounts of thetwo calcium phosphates and the appropriate weight percent of Ca₅ (PO₄)₃OH was mixed with 0.5 ml of the appropriate H₃ PO₄ solution. All of thespecimens were stirred into pastes, allowed to harden, and were soakedin H₂ O at 37° C. for twenty-four hours. The compressive strengths inpounds per square inch were then determined as shown in Table I.

EXAMPLE 5

Specimens 6-9 shown in Table II were prepared by grinding Ca₄ (PO₄)₂ O,CaHPO₄.2H₂ O, and Ca₅ (PO₄)₃ OH to a mean particle size of 5 μm. Onegram of a mixture containing equimolar amounts of Ca₄ (PO₄)₂ O andCaHPO₄.2H₂ O and the appropriate weight percent of Ca₅ (PO₄)₃ OH wasmixed with 0.5 ml of 20mM H₃ PO₄ to form a paste. This paste was thenallowed to harden. The setting times as a function of apatite seedcontent are shown in Table II.

EXAMPLE 6

To form a porous cement of increased strength, Ca₄ (PO₄)₂ O andCaHPO₄.2H₂ O are ground to a mean particle size of 5 μm. Two grams of amixture containing equimolar amounts of the two calcium phosphates and0.5 gram of granular sugar (or another highly water soluble material)are mixed and placed in a mold.

                                      TABLE I                                     __________________________________________________________________________    COMPRESSIVE STRENGTHS OF EXPERIMENTAL CEMENTS                                                     Ca.sub.5 (PO.sub.4).sub.3 OH, Wt %                                                               Compressive Strength                   Specimen                                                                           Calcium Phosphates                                                                           Seed Content                                                                             Solution                                                                              (PSI).sup.1                            __________________________________________________________________________    1    CaHPO.sub.4.2H.sub.2 O + Ca.sub.4 (PO.sub.42)O                                               0           5 mM H.sub.3 PO.sub.4                                                                4390 ± 860 (3)                      2    CaHPO.sub.4.2H.sub.2 O + Ca.sub.4 (PO.sub.4).sub.2 O                                         0          20 mM H.sub.3 PO.sub.4                                                                4560 ± 520 (3)                      3    CaHPO.sub.4 + Ca.sub.4 (PO.sub.4).sub.2 O                                                    0          20 mM H.sub.3 PO.sub.4                                                                4960 ± 650 (3)                      4    CaHPO.sub.4 + Ca.sub.4 (PO.sub.4).sub.2 O                                                    2.7        20 mM H.sub.3 PO.sub.4                                                                4280 ± 940 (2)                      5    CaHPO.sub.4 + Ca.sub.4 (PO.sub.4).sub.2 O                                                    9.6        20 mM H.sub.3 PO.sub.4                                                                 4578 ± 1010 (2)                    __________________________________________________________________________     .sup.1 Compressive strengths are shown as mean value ± standard            deviation. The number of samples is shown in parentheses.                

                  TABLE II                                                        ______________________________________                                        SETTING TIME AS A FUNCTION OF                                                 HYDROXYAPATITIC SEED CONTENT                                                  FOR EXPERIMENTAL CEMENTS                                                                                  Setting Time.sup.1                                Specimen Ca.sub.5 (PO.sub.4).sub.3 OH Content, Wt %                                                       Min.                                              ______________________________________                                        6         0                 22                                                7        24                 11                                                8        34                  9                                                9        43                  8                                                ______________________________________                                         .sup.1 The setting times were measured according to American Dental           Association Specification No. 9.                                         

Usually addition of water to the mixture is not needed but a smallamount may be added in some instances to facilitate the settingreaction. Up to 80,000 pounds per square inch of pressure is applied tothe cement mixture using a press for two minutes. The specimen, which ismade into a compact mass by the process, is placed in boiling water toextract the water soluble granules and to complete the setting process.The resulting porous materials can be used as protheses which can beinvaded more readily by organic bone tissue.

It should be understood that the foregoing disclosure emphasizes certainspecific embodiments of the invention and that all modifications ofalternatives equivalent thereto are within the spirit or scope of theinvention.

We claim as our invention:
 1. A dental restorative paste comprising anaqueous mixture of Ca₄ (PO₄)O and at least one other calcium phosphateselected from the group consisting of CaHPO₄.2H₂ O, CaHPO₄, Ca₈ H₂(PO₄)₆.5H₂ O, α-Ca₃ (PO₄)₂, β-Ca₃ (PO₄)₂, and modified Ca₃ (PO₄)₂, thepaste being capable of hardening into a cement.
 2. The paste of claim 1wherein the other calcium phosphate is CaHPO₄.2H₂ O.
 3. The paste ofclaim 1 wherein the other calcium phosphate is CaHPO₄.
 4. The paste ofclaim 1 wherein the other calcium phosphate is Ca₈ H₂ (PO₄)₆.5H₂ O. 5.The paste of claim 1 wherein the other calcium phosphate is β-Ca₃(PO₄)₂.
 6. The paste of claim 1 wherein both calcium phosphates are incrystalline, cryptocrystalline, or amorphous form.
 7. The paste of claim1 further comprising up to approximately 10% by weight of additionalcalcium or phosphate containing compounds.
 8. The paste of claim 7wherein the additional calcium containing compounds comprise CaCl₂ orCa(C₂ H₃ O₂)₂.
 9. The paste of claim 7 wherein the additional phosphatecontaining compounds comprise NaH₂ PO₄ or (NH₄)H₂ PO₄.
 10. The paste ofclaim 1 further comprising fluoride containing compounds such that thefluoride content of the paste is up to approximately 3.8% by weight. 11.The paste of claim 10 wherein the fluoride containing compounds compriseCaF₂, SrF₂, NaF, Na₂ SiF₆ or NaPO₃ F.
 12. A paste comprising CaHPO₄ andCa₄ (PO₄)₂ O having a particle size of approximately 1 μm and a 20mMsolution of H₃ PO₄.
 13. The paste of claim 1 additionally comprising aseed crystal compound selected from the group consisting ofhydroxyapatite and fluorapatite.